While both cross-sectional and short-term longitudinal studies have observed declines in cognitive functioning leading to dementia in healthy elderly individuals, we are still lacking sensitive and specific biological markers for the pre-clinical stages of AD. This need continues to negatively impact on research and the management of changes or a characterized and altered physiology while being relative insensitive to the effects of age. We propose to identify and evaluate such a set of potential markers in transgenic mice (PS/APP) that have extensive beta- amyloidosis. The mice show extensive amyloidosis, which begins at three months of age, and continues to build throughout their life span. The levels of amyloid present in the brain in later life far exceeds that found in human AD brain, but over neurodegeneration has not been seen by cell counting paradigms. In the proposed study, we will systematically characterize tissue changes in brain regions from transgenic mice that exhibit beta-amyloid deposition and compare them to regions that are free of such changes. Our objectives are to provide anatomically, physiologically, and neuropathologically valid neuroimaging markers to characterize the stages of brain involvement. Our research plan will begin with studies that utilize MRI to characterize the effects of beta-amyloid deposition. In a longitudinal imaging design, we will use MRI to characterize the effect of progressive beta-amyloid deposition on the biophysical environment of water in brain. Moreover, we will extend our well-established perfusion and diffusion MRI imaging protocols from the rat to the mouse along with two types of validation studies. First, we will characterize regional glucose utilization in the PS/APP mouse using [14C] 2-deoxyglucose (14C-2DG), and second, by sampling over time from the longitudinal cohort of animals, we will utilize unbiased stereology to estimate neuronal numbers, the extend of gliosis, and amyloid burden as a function of transgenic strain and age of the animal. Overall, it is expected that this work will provide us with a better understanding of the effects of the transgenic model and beta-amyloid burden on brain structure and brain function. This new capability will enable us to develop the tools to non-invasively assess new animal models as well as the efficacy of therapeutic interventions. This type of pursuit could potentially aid the translation of these findings into improved clinical diagnosis and management.